This invention relates to pyrrolidin-2-ylcarbonylheterocyclic compounds and their physiologically acceptable salts which exhibit inhibitory activity on prolyl endopeptidase and are useful for the treatment of amnesia or Alzheimer's Disease. The compounds are also useful as cognitive enhancers and assist in memory retention.
It is hitherto known that prolyl endopeptidase (PEP) [EC 3.4.21.26] has the substrate specificity on peptide hormones which contain proline like substance P, thyrotropin releasing hormone, neurotensin and vasopressin, and inactivates them. Among the above peptides vasopressin is considered to be concerned with memory process (Life Science, vol. 19, p. 685 (1976) and Science, vol. 221, p. 601 (1981)). Yoshimoto et al. reported that inhibitors against PEP are effective on experimental amnesia in rats and PEP inhibitors are concerned with memory process (Seikagaku, vol. 55, p. 831 (1983), Nippon Nogeikagaku Katshi, vol. 58, p. 1147 (1984) and Japanese Patent Application Laid-open (Kokai) No. 172929/1985). From the above facts it seemed to be possible that PEP inhibitors are useful on the treatment and prevention of amnesia (Journal of Pharmacobio-Dyn, vol. 10, p. 730 (1987)).
On the other hand some pyrrolidine analogs which have 2-chloromethylcarbonyl, 2-diazomethylcarbonyl or 2-formyl residue on their carboxyl terminal ends are reported to have PEP-inhibitory activity (Biochemistry, vol. 16, p. 2942 (1977) and Journal of Neurochemistry, vol. 41, p. 69 (1983)). Furthermore, related amino acid analogs which have a--COCO.sub.2 R, --COCONR'R", --COCF.sub.3, --COCF.sub.2 CO.sub.2 R or --COCF.sub.2 NR'R" residue on the carboxyl terminal end are reported but there are no descriptions on PEP inhibiting activity (European Patent Application No. 320753/1989).